recognition of occluded object using wavelets

TYPICAL AND ATYPICAL ANTIPSYCHOTICS: ROLE OF THE NORADRENERGIC SYSTEM IN THE TREATMENT OF SCHIZOPHRENIA VIVEK VERMA (MBBS, DELHI UNIVERSITY) A THESIS SUBMITTED FOR THE DEGREE OF PhD DEPARTMENT OF PHARMACOLOGY NATIONAL UNIVERSITY OF SINGAPORE 2006 ACKNOWLEDGEMENT I would like to thank my supervisor, Dr Gavin Dawe for guiding me through the whole duration of my PhD and encouraging me in my work. I would also like to thank all the people associated with the laboratory as well as the department of pharmacology for their cooperation. Finally I would like to thank the National University of Singapore for providing me with an opportunity to pursue my research work. TABLE OF CONTENTS ACKNOWLEDGEMENTS…………………………………………………………1 TABLE OF CONTENTS…………………………………………………………….2 SUMMARY…………………………………………………………………………….5 LIST OF FIGURES…………………………………………………………… .…….7 ABBREVIATIONS…………………………………………………………….…….10 CHAPTER 1. INTRODUCTION………………………………………………….11 1.1 SCHIZOPHRENIA………………………………………………………………… 11 1.1.1. Disease and History………………………………………………………….11 1.1.2. Signs and Symptoms…………………………………………… .………….12 1.1.3. Treatment of Schizophrenia………………………………………………….14 1.2 THEORIES OF SCHIZOPHRENIA……………………………………………… .16 1.2.1. The Dopaminergic Pathway…………………………………………………16 1.2.2. The Serotonergic Pathway………………………………………………… .16 1.2.3. The Glutaminergic Pathway…………………………………………………17 1.2.4. The GABAergic Pathway……………………………………………………18 1.2.5. The Noradrenergic Pathway…………………………………………………18 1.3 ANIMAL RESEARCH IN SCHIZOPHRENIA…………………………………….19 1.3.1 Animal Models of Schizophrenia……………………………………………19 1.3.2 Prepulse Inhibition (PPI) .………………………………………………… 21 1.3.3 Latent Inhibition…………………………………………………………… 22 1.3.4 Morris Water Maze………………………………………………………… 23 1.3.5 Immediate Early Gene (IEG) Expression .………………………………….25 1.4 NORADRENERGIC THEORY OF SCHIZOPHRENIA………………………… .27 1.4.1 Role of Noradrenergic System in PPI…………… . ……………………… 27 1.4.2 Noradrenergic System and IEG Expression .……………………………….29 1.4.3 Noradrenergic System and Performance in the Water Maze……………… .31 1.5 AIM OF THE THESIS………………………………………………………………33 CHAPTER 2. METHODOLOGY…………………………………………………35 2.1 IMMUNOSTAINING EXPERIMENTS…………………………………………….35 2.1.1 Comparison between typical and atypical antipsychotics………………… .35 2.1.2 Effect of different dosages and treatment durations of Olanzapine on IEG and the TH expression……………………………………………………………………39 2.2 CHAKRAGATI MOUSE EXPERIMENTS…………………………………………41 2.2.1 LI…………………… ………………………………………………………41 2.2.2 PPI……………………………………………………………………………44 2.3 RAT EXPERIMENTS…………………………………………………………….…47 2.3.1 Subjects…………………………………………………………………… 47 2.3.2 Drug Treatment………………………………………………………………48 2.3.3 Prepulse Inhibition Study…………………………………………………….50 2.3.4 Water Maze Study……………………………………………………………50 CHAPTER 3. RESULTS……………………………………………………………53 3.1 IMMUNOHISTOCHEMISTRY EXPERIMENTS……………………… .……… 56 3.1.1 Comparison between typical and atypical antipsychotics…… …………….53 3.1.2 Effect of different dosages and treatment durations of olanzapine on IEG and TH expression……………………………………………………………………… 64 3.2 CHAKRAGATI MOUSE EXPERIMENTS…………………………………………76 3.2.1 Validity Experiments……………………………………………………… .76 3.2.2 Drug Experiments……………………………………………………………80 3.3 RAT EXPERIMENTS……………………………………………………………….85 3.3.1 Water Maze Experiments…………………………………………………….85 3.3.2 PPI Experiments…………………………………………………………… .94 CHAPTER 4. DISCUSSION…………………………………………………….…98 CHAPTER 5. CONCLUSIONS …………………………………………………120 REFERENCES…………………………………………………………………… .123 SUMMARY Currently two broad categories of drugs known as “typical antipsychotics” and “atypical antipsychotics” are used in the treatment of schizophrenia. The typical (e.g. haloperidol) were the first to be used and are known to be effective in treating the positive symptoms of the disease. The atypicals (e.g. clozapine, olanzapine) are the newer drugs and are genetally more effective in treating the negative symptoms. The exact cause of better efficacy of the atypical drugs is not precisely known. In my research work, I have focused on the role of the noradrenergic system. I have investigated the effect of antipsychotics on immediate early gene (IEG) and tyrosine hydroxylase (TH) expression in the medial prefrontal cortex (mPFC) and locus coeruleus (LC) in rat brain. In addition I validated an animal model of schizophrenia by conducting prepulse inhibition (PPI) and latent inhibition (LI) studies in the genetically modified “chakragati (ckr)” mice. Effects of antipsychotic drugs and noradrenergic drugs on the PPI in these mice were also studied. In the last part of the thesis, experiments were conducted to study the effect of antipsychotic drugs and noradrenergic drugs on the PPI and water maze performance in an N-methyl-D-aspartic acid (NMDA) antagonist induced model of schizophrenia. The study involving the IEG expression changes demonstrated that atypical and typical antipsychotics differ qualitatively in their effects on IEG and TH expression in the mPFC and LC. In particular, the atypical antipsychotics, risperidone and clozapine, produce greater increases in TH expression in the LC and mPFC than the typical antipsychotic, haloperidol. I also charted effects of different olanzapine doses and treatment durations on IEG and TH protein expression in the mPFC and LC of the rat. There are immediate as well as delayed dose-dependent effects of olanzapine on the patterns of expression. Future investigation of how changes in IEG and TH expression correlate with each other in the mPFC and to prefrontal cortical dependent behaviours is required. It was found that the ckr mice have disrupted LI and PPI. These effects were attributed to sensorimotor gating defects. I further showed that atypical antipsychotics were more successful in reversing the PPI defects than the typical antipsychotics. Over all the ckr mice has given indication that in future it could serve as a useful animal model of schizophrenia. The experiments with adrenergic drugs, both in ckr mice as well as rats, show an additive effect of the alpha1 antagonist, prazosin, and atypical antipsychotics in reversing PPI deficits. In spatial memory tests in rats, there seemed to be an additive effect of the alpha2 antagonist, idazoxan, with the atypical antipsychotics, in improving the water maze performance. Starting from IEG expression to behavior testing in animals, a role for adrenergic system is visible in the patho-psysiology as well as treatment of schizophrenia. The additive effects of adrenergic drugs to the atypical antipsychotic drugs is encouraging and has the potential to develop into a novel therapeutic regime. LIST OF FIGURES 1. Drawings of regions of the prelimbic (PrL) area of the medial prefrontal cortex and Locus Coeruleus (LC) ……………………………………………………………… ….55 2. Effects of 4-week antipsychotic drug treatment on c-Fos expression in the medial prefrontal cortex (mPFC) and the locus coeruleus (LC)……………………………… .56 3. Showing c-Fos Expression with a) Clozapine and b) Haloperidol……………………57 4. Counting of c-Fos immunoreactive nuclei…………………………………………….57 5. Photomicrographs of immunostaining with anti-c-Fos antibody in the mPFC following chronic treatment……………………………………………………………………… .58 6. Effects of 4-week antipsychotic drug treatment on Egr-1 expression in the mPFC and the LC…………………………………………………………………………………….59 7. Effects of 4-week antipsychotic drug treatment on Egr-2 expression in the mPFC and the LC…………………………………………………………………………………….60 8. Photomicrographs of immunostaining with anti-Egr-1 antibody in mPFC….……… 61 9. Photomicrographs of immunostaining with anti-Egr-2 antibody in LC………………61 10. Effects of 4-week antipsychotic drug treatment on tyrosine hydroxylase (TH) expression in the mPFC and the LC…………………………….……………………….62 11. Illustration of the immunostainning for TH…………………………………………63 12. Brain regions within which various IEG immunoreactive nuclei and TH immunoreactive profiles were counted………………………………………………….68 13. Effects of olanzapine dose and treatment duration on c-Fos immunoreactivity in the LC and the mPFC……………………………………………………………………….69 14. Effects of olanzapine dose and treatment duration on c-Jun immunoreactivity in the LC and the mPFC……………………………………………………………………… 70 15. Effects of olanzapine dose and treatment duration on ATF-2 immunoreactivity in the LC and the mPFC……………………………………………………………………… 71 16. Effects of olanzapine dose and treatment duration on Egr-1 immunoreactivity in the LC and the mPFC…………………………………………………………………….….72 17. Effects of olanzapine dose and treatment duration on Egr-2 immunoreactivity in the LC and the mPFC……………………………………………………………………… 73 18.Effects of olanzapine dose and treatment duration on tyrosine hydroxylase (TH) immunoreactivity in LC and mPFC…………………………………………………… 74 19. Representative photomicrographs of serial sections through the LC immunostained for (a) Egr-1 and (b) TH…………………………………………………………………75 20. Representative photomicrographs of TH immunoreactivity in the LC……… …….75 21. Effects of gene manipulation on the Prepulse Inhibition in experimental mice (wild type, heterozygous and homozygous)……………………………………………………76 22. Effects of gene manipulation on the startle amplitude in experimental mice (wild type, heterozygous and homozygous)………………………………………………………….77 23. Effects of different time gaps between prepulse and the pulse tones, on the Prepulse Inhibition in experimental mice (homozygous strain)………………………………… .78 24. Effects of gene manipulation on the Latent Inhibition in experimental mice (wild type, heterozygous and homozygous)………………………………………………………….79 25. Effect of antipsychotic drug treatment on the PPI of wild type as well as the homozygous strain of chakra mice………………………………………………………81 26. Effect of antipsychotic treatment on the startle amplitude of wild type mice……….81 27. Effect of antipsychotic treatment on startle amplitude of homo. chakra mice…… 82 28. Effect of adrenergic drug treatment on the PPI of wild type as well as the homozygous strain of chakra mice………………………………………………………83 29. Effect of adrenergic treatment on the startle amplitude of wild type mice………….84 30. Effect of adrenergic treatment on startle amplitude of homozygous chakra mice… 84 31. Effects of chronic exposure to antipsychotic drug treatments on latency to find a hidden platform in a water maze task on consecutive days of testing compared to vehicle controls……………………………………………………………………….….86 32. Effects of chronic exposure to antipsychotic drug treatments on the swim distance to find a hidden platform in a water maze task on consecutive days of testing compared to vehicle controls………………………………………………………………………… 87 33. Effects of chronic exposure to antipsychotic drug treatments on swim speed while trying to find a hidden platform in a water maze task on consecutive days of testing compared to vehicle controls. ………………………………………………………… .88 34. Effects of chronic exposure to adrenergic drug treatments on latency while trying to find a hidden platform in a water maze task on consecutive days of testing………… 91 35. Effects of chronic exposure to adrenergic drug treatments on swim distance while trying to find hidden platform in water maze task on consec. days of testing…………92 36. Effects of chronic exposure to adrenergic drug treatments on swim speed while trying to find a hidden platform in a water maze task on consecutive days of testing…….….93 37. Effect of various antipsychotic treatments on the prepulse inhibition in rats……… 95 38. Effect of various antipsychotic treatments on the startle amplitude in rats………….95 39. Effect of various adrenergic treatments on the prepulse inhibition in rats………… 97 40. Effect of various adrenergic treatments on the startle amplitude in rats…………… 97 Killcross AS, Dickinson A, Robbins TW. (1994). 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Lim EP, Verma V, Nagarajah R, Dawe GS Psychopharmacology (Berl). 2007 Jan 16; [Epub ahead of print] 149 [...]... previous level of functioning; (iii) chronicity of the disorder for at least 6 month; (iv) a tendency toward onset before the age of 45; (v) symptoms not due to mood (affective) disorders; and (vi) symptoms not due to organic mental disorder or mental retardation (American Psychiatric Association, 1994) The incidence of schizophrenic disorders varies depending on the breadth of criteria used Using a relatively... affected by lots of factors and these should be considered before comparing the results of any two experiments These factors could be the sex of the animal, their strain, the dimensions of the pool which has been used for the experiment, the temperature of the water when the experiment were conducted and the particular training schedule which was followed during the study (Wenk, 1998) The results of the test... overemphasis of normal movements are more common There may be abnormalities of psychomotor activities; eg, rocking, pacing, peculiar motor responses and even immobility 13 Violent behavior: In acute schizophrenic states and relapses, minor aggression and threats of violence are common but dangerous behavior when the patient obeys commanding voices is uncommon The risk of suicide is increased in all stages of. .. suicide is increased in all stages of schizophrenia Ten percent of schizophrenic patients commit suicide 1.1.3 Treatment of Schizophrenia Current treatment of schizophrenia relies primarily on somatic drug therapy But the pharmacological treatment of schizophrenia did not begin, however, until approximately a century ago Before this, all kinds of mental illnesses were thought to be related to religious... dedicated to investigation of this pathway All the experiments were conducted to investigate role of the noradrenergic pathway in the actions of drugs used to treat schizophrenia Noradrenaline is a catecholamine found in high concentrations throughout the nervous system The system consists of a positive and negative feedback circuits, which affects the concentration levels of both noradrenaline as well... of sight, touch, smell and taste may occur Specifically the hallucinations of a running commentary on the patient’s actions or of voices talking about the patient, strongly suggest schizophrenia Poverty of speech is commonly reported, and ritualistic behavior associated with magical thinking often occurs Delusions: Delusions of persecution are frequent, as are those involving hypochondriacal or religious... waves of gene expression IEGs and their proteins are links through which external stimuli can alter the gene transcription process within a cell A large number of IEGs have been identified A few of them for example, c-fos, c-jun and egr-1 fall under the category of “transcription factors” These are DNA binding proteins having several related homologs (Hai and Curran, 1991; Nakabeppu et al, 1988) Most of. .. Affinity of each of these complexes for the AP-1 site is different from the others (Hai and Curran, 1991; Kovary and Bravo, 1991; Ryseck and Bravo, 1991) Also these complexes sometimes undergo posttranslational modifications that further enhance their ability to affect the transcription process in a more diverse way (Barber and Verma, 1987; Ofir et al, 1990; Boyle et al, 1991) Induction of expression of. .. reported to exhibit beta agonist activity, this suggests that activation of the LC, the major source of noradrenergic innervation of the prefrontal cortex (Berridge and Waterhouse, 2003), and release of noradrenaline is instrumental in inducing this Fos-like activity in the mPFC Consistent with this hypothesis, acute administration of atypical antipsychotics has been shown to increase c-Fos and Fos-like... memory deficits of 24 month old rats to a level that was compatible with that of adult animals In a separate experiment Chopin et al (2004) again showed the protective effects of dexefaroxan against spatial memory deficit induced by cortical devascularization in the adult rat A few studies have also implicated the role of alpha-1 adrenoceptors Puumala et al (1998) showed that administration of St-587 (a . 7 LIST OF FIGURES 1. Drawings of regions of the prelimbic (PrL) area of the medial prefrontal cortex and Locus Coeruleus (LC) ……………………………………………………………… ….55 2. Effects of 4-week antipsychotic. startle amplitude of wild type mice……….81 27. Effect of antipsychotic treatment on startle amplitude of homo. chakra mice…… 82 28. Effect of adrenergic drug treatment on the PPI of wild type. strain of chakra mice………………………………………………………83 29. Effect of adrenergic treatment on the startle amplitude of wild type mice………….84 30. Effect of adrenergic treatment on startle amplitude of